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38


Prospective individual patient data meta-analysis: Evaluating convalescent plasma for COVID-19

Goldfeld, Keith S; Wu, Danni; Tarpey, Thaddeus; Liu, Mengling; Wu, Yinxiang; Troxel, Andrea B; Petkova, Eva
As the world faced the devastation of the COVID-19 pandemic in late 2019 and early 2020, numerous clinical trials were initiated in many locations in an effort to establish the efficacy (or lack thereof) of potential treatments. As the pandemic has been shifting locations rapidly, individual studies have been at risk of failing to meet recruitment targets because of declining numbers of eligible patients with COVID-19 encountered at participating sites. It has become clear that it might take several more COVID-19 surges at the same location to achieve full enrollment and to find answers about what treatments are effective for this disease. This paper proposes an innovative approach for pooling patient-level data from multiple ongoing randomized clinical trials (RCTs) that have not been configured as a network of sites. We present the statistical analysis plan of a prospective individual patient data (IPD) meta-analysis (MA) from ongoing RCTs of convalescent plasma (CP). We employ an adaptive Bayesian approach for continuously monitoring the accumulating pooled data via posterior probabilities for safety, efficacy, and harm. Although we focus on RCTs for CP and address specific challenges related to CP treatment for COVID-19, the proposed framework is generally applicable to pooling data from RCTs for other therapies and disease settings in order to find answers in weeks or months, rather than years.
PMID: 34164838
ISSN: 1097-0258
CID: 4918612

A constrained single-index regression for estimating interactions between a treatment and covariates

Park, Hyung; Petkova, Eva; Tarpey, Thaddeus; Ogden, R Todd
We consider a single-index regression model, uniquely constrained to estimate interactions between a set of pretreatment covariates and a treatment variable on their effects on a response variable, in the context of analyzing data from randomized clinical trials. We represent interaction effect terms of the model through a set of treatment-specific flexible link functions on a linear combination of the covariates (a single index), subject to the constraint that the expected value given the covariates equals zero, while leaving the main effects of the covariates unspecified. We show that the proposed semiparametric estimator is consistent for the interaction term of the model, and that the efficiency of the estimator can be improved with an augmentation procedure. The proposed single-index regression provides a flexible and interpretable modeling approach to optimizing individualized treatment rules based on patients' data measured at baseline, as illustrated by simulation examples and an application to data from a depression clinical trial. This article is protected by copyright. All rights reserved.
PMID: 32573759
ISSN: 1541-0420
CID: 4493012

Extracting scalar measures from functional data with applications to placebo response

Tarpey, Thaddeus; Petkova, Eva; Ciarleglio, Adam; Ogden, Robert Todd
In controlled and observational studies, outcome measures are often observed longitudinally. Such data are difficult to compare among units directly because there is no natural ordering of curves. This is relevant not only in clinical trials, where typically the goal is to evaluate the relative efficacy of treatments on average, but also in the growing and increasingly important area of personalized medicine, where treatment decisions are optimized with respect to a relevant patient outcome. In personalized medicine, there are no methods for optimizing treatment decision rules using longitudinal outcomes, e.g., symptom trajectories, because of the lack of a natural ordering of curves. A typical practice is to summarize the longitudinal response by a scalar outcome that can then be compared across patients, treatments, etc. We describe some of the summaries that are in common use, especially in clinical trials. We consider a general summary measure (weighted average tangent slope) with weights that can be chosen to optimize specific inference depending on the application. We illustrate the methodology on a study of depression treatment, in which it is difficult to separate placebo effects from the specific effects of the antidepressant. We argue that this approach provides a better summary for estimating the benefits of an active treatment than traditional non-weighted averages.
PMCID:8313021
PMID: 34316322
ISSN: 1938-7989
CID: 4949372

A sparse additive model for treatment effect-modifier selection

Park, Hyung; Petkova, Eva; Tarpey, Thaddeus; Ogden, R Todd
Sparse additive modeling is a class of effective methods for performing high-dimensional nonparametric regression. This article develops a sparse additive model focused on estimation of treatment effect modification with simultaneous treatment effect-modifier selection. We propose a version of the sparse additive model uniquely constrained to estimate the interaction effects between treatment and pretreatment covariates, while leaving the main effects of the pretreatment covariates unspecified. The proposed regression model can effectively identify treatment effect-modifiers that exhibit possibly nonlinear interactions with the treatment variable that are relevant for making optimal treatment decisions. A set of simulation experiments and an application to a dataset from a randomized clinical trial are presented to demonstrate the method.
PMID: 32808656
ISSN: 1468-4357
CID: 4566752

A Bayesian Approach to Joint Modeling of Matrix-valued Imaging Data and Treatment Outcome with Applications to Depression Studies

Jiang, Bei; Petkova, Eva; Tarpey, Thaddeus; Ogden, R Todd
In this paper we propose a unified Bayesian joint modeling framework for studying association between a binary treatment outcome and a baseline matrix-valued predictor. Specifically, a joint modeling approach relating an outcome to a matrix-valued predictor through a probabilistic formulation of multilinear principal component analysis (MPCA) is developed. This framework establishes a theoretical relationship between the outcome and the matrix-valued predictor although the predictor is not explicitly expressed in the model. Simulation studies are provided showing that the proposed method is superior or competitive to other methods, such as a two-stage approach and a classical principal component regression (PCR) in terms of both prediction accuracy and estimation of association; its advantage is most notable when the sample size is small and the dimensionality in the imaging covariate is large. Finally, our proposed joint modeling approach is shown to be a very promising tool in an application exploring the association between baseline EEG data and a favorable response to treatment in a depression treatment study by achieving a substantial improvement in prediction accuracy in comparison to competing methods. This article is protected by copyright. All rights reserved.
PMID: 31529701
ISSN: 1541-0420
CID: 4089132

A single-index model with multiple-links

Park, Hyung; Petkova, Eva; Tarpey, Thaddeus; Ogden, R Todd
In a regression model for treatment outcome in a randomized clinical trial, a treatment effect modifier is a covariate that has an interaction with the treatment variable, implying that the treatment efficacies vary across values of such a covariate. In this paper, we present a method for determining a composite variable from a set of baseline covariates, that can have a nonlinear association with the treatment outcome, and acts as a composite treatment effect modifier. We introduce a parsimonious generalization of the single-index models that targets the effect of the interaction between the treatment conditions and the vector of covariates on the outcome, a single-index model with multiple-links (SIMML) that estimates a single linear combination of the covariates (i.e., a single-index), with treatment-specific nonparametric link functions. The approach emphasizes a focus on the treatment-by-covariates interaction effects on the treatment outcome that are relevant for making optimal treatment decisions. Asymptotic results for estimator are obtained under possible model misspecification. A treatment decision rule based on the derived single-index is defined, and it is compared to other methods for estimating optimal treatment decision rules. An application to a clinical trial for the treatment of depression is presented.
PMCID:7441812
PMID: 32831459
ISSN: 0378-3758
CID: 4575092

Adolescent-Specific Motivation Deficits in Autism Versus Typical Development

Bos, Dienke J; Silver, Benjamin M; Barnes, Emily D; Ajodan, Eliana L; Silverman, Melanie R; Clark-Whitney, Elysha; Tarpey, Thaddeus; Jones, Rebecca M
Differences in motivation during adolescence relative to childhood and adulthood in autism was tested in a cross-sectional study. 156 Typically developing individuals and 79 individuals with autism ages 10-30 years of age completed a go/nogo task with social and non-social cues. To assess age effects, linear and quadratic models were used. Consistent with prior studies, typically developing adolescents and young adults demonstrated more false alarms for positive relative to neutral social cues. In autism, there were no changes in attention across age for social or non-social cues. Findings suggest reduced orienting to motivating cues during late adolescence and early adulthood in autism. The findings provide a unique perspective to explain the challenges for adolescents with autism transitioning to adulthood.
PMID: 31625010
ISSN: 1573-3432
CID: 4140682

Optimising treatment decision rules through generated effect modifiers: a precision medicine tutorial

Petkova, Eva; Park, Hyung; Ciarleglio, Adam; Todd Ogden, R; Tarpey, Thaddeus
This tutorial introduces recent developments in precision medicine for estimating treatment decision rules. The objective of these developments is to advance personalised healthcare by identifying an optimal treatment option for each individual patient based on each patient's characteristics. The methods detailed in this tutorial define composite variables from the patient measures that can be viewed as 'biosignatures' for differential treatment response, which we have termed 'generated effect modifiers'. In contrast to most machine learning approaches to precision medicine, these biosignatures are derived from linear and non-linear regression models and thus have the advantage of easy visualisation and ready interpretation. The methods are illustrated using examples from randomised clinical trials.
PMID: 31791433
ISSN: 2056-4724
CID: 4218142

EFFECTS OF EPINEPHRINE ON SIMULTANEOUS, REAL TIME END-TIDAL CARBON DIOXIDE TENSION AND CEREBRAL OXIMETRY MONITORING DURING RESUSCITATION OF IN HOSPITAL CARDIAC ARREST [Meeting Abstract]

Reddy, V; Roellke, E; Qian, Y; Dupont, D; McMullin, M; VASCONCELOS, R; Lam, J; Walsh, B; Williams, T; Tarpey, T; Deakin, C; Parnia, S
SESSION TITLE: Wednesday Abstract Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/23/2019 09:45
EMBASE:2002982868
ISSN: 1931-3543
CID: 4119242

Letter to the Editor

Tarpey, Thaddeus; Petkova, Eva
Hutson and Vexler (2018) demonstrate an example of aliasing with the beta and normal distribution. This letter presents another illustration of aliasing using the beta and normal distributions via an infinite mixture model, inspired by the problem of modeling placebo response.
PMCID:7986476
PMID: 33762775
ISSN: 0003-1305
CID: 4822762